IL37588A

IL37588A - 2h-pyrimido (2,1-a) isoquinolin-2-ones,their preparation and pharmaceutical compositions containing them

Info

Publication number: IL37588A
Application number: IL37588A
Authority: IL
Original assignee: Wellcome Found
Priority date: 1970-08-27
Filing date: 1971-08-26
Publication date: 1974-09-10
Also published as: ES394546A1; BE771911A; AR193522A1; US3792050A; IL37588A0; SE373138B; IE35570B1; NL7111759A; FR2103559A1; ES422327A1; DE2142792A1; GB1356937A; AR195669A1; AR192890A1; FR2103559B1; CA977343A

Description

,o'»jiK-a- ia'3it»« £ a —1,2] n'a' ..^ .oniK o'V'aan nnnpn 'Twsm aruan 2H-P rimido [ 2fl-a ] isoquinoline-2-ones, their preparation and pharmaceutical compositions containing them.

THE WELCOME FOUHDATIOIT LIMITED C. 35606 This invention relates to pyrimido { 2 , 1-a} isoquinolines , their synthesis, and pharmaceutical compositions containing them.

The compounds of this invention have the chemical structure shown in formula (I) 1 2 wherein X and X. are each a hydrogen atom or together they form an additional bond.

These compounds and their acid addition salts (hereinafter referred to as the"invented compounds") have been found to have anti-inflammatory activity in mammals. In particular, the invented compounds upon oral administration, reduce the inflammation associated with the development of both primary and secondary lesions in rats with adjuvant-induced arthritis. The invented compounds are especially active in reducing the inflammation associated with secondary lesions.

Compounds having these properties are used in the treatment of inflammatory and arthritic diseases.

The anti-inflammatory activity of the invented compounds resides in the base, and the acid of the acid addition salts is of less importance though it should be chosen such that an acid addition salt is pharmacologically and pharmaceutically acceptable. For example, the acid may be a mineral acid, for example hydrochloric or sulphuric acid, or a strong organic acid, for example a carboxylic The invented compounds may be prepared by any method known for the preparation of compounds of analogous chemical structure. reaction of Thus the invent compound of formula (II) wherein X and X have the same meaning as before, with an alkyl acrylate ester of the formula (III) CH =CH.C00R (III) wherein R is an alkyl group having 1 i.o 6 carbon atoms, preferably a primary alkyl. group. The reaction is optionally carried out in the presence of a solvent, a polar solvent being preferred. The reactants may be present in an equimolar amount, but an excess of an ester of formula (III) may be used.

The invented compounds may also be prepared, in the presence of a solvent if desired, by the reaction of a 0-substituted propionate ester of formula (IV) CH2.CH2.COOR (IV) with a compound of formula (II) . In formula (IV) , R is an alkyl group and Z is a nucleophilic atom or group, preferably a halogen atom, for example chlorine, bromine or iodine or a toluenesulphonyl group. The reactants may be present in equimolar quantities but an excess of the ester may be used.

The invented compound may also be made by ring closure of the ' appropriate compound of formula wherein X an X ave t e same mean ng as e ore. R ng closure is most readily effected by heating a compound of formula (V) above its melting point, for example about 200°C, or by treatment with an acid, conveniently at . a temperature below 100°C. Preferably a . concentrated mineral acid, for example such as p-toluenesulphonic acid may be used.

The intermediates of formula (V) may be prepared by the reaction of a compound of formula (II) with acrylic acid, β-propiolactone , or β-hydroxypropionic acid. The reaction is carried out conveniently in a polar solvent such as water , or an aliphatic ketone for example acetone, preferably using equimolar quantities of the reactan.ts and if desired using heating..

It will be understood from the preceding two paragraphs, that the intermediate compounds of formula (.V). , may be prepared in situ and converted to the compounds of formula (I) , without the necessity of isolating the intermediate compounds of formula (v).

The invented compounds may also be prepared by oxidation of reduced forms of the compounds. Thus 3 , 4-dihydro-2-oxo-2H-pyrimido— {2,l-a}isoquirioline may be prepared by oxidation, at an elevated temperature with a palladium catalyst , conveniently palladium black, · of a compound of formula (VI) ; and 3 , 4 , 6 , 7-Tetrahydro-2-oxo-2H-pyrimido { 2 , 1-a} isoquinoline by oxidation at room temperature with iodine of the compound of formula (VI) .

The invented compounds may be isolated from the reaction mixture formed upon completion of a preparative process described above, either as the base or as an acid addition salt thereof. The product may then be converted, if desired, into the other form; thus the base may be converted into an acid addition salt thereof or vice versa; or ah acid addition salt converted into the salt of another acid by double decomposition. These reactions may be carried out by standard chemical procedures, for example, in solution or on an ion exchange column.

For the treatment of an animal, for example a human, the invented compounds may be presented with an acceptable carrier therefor as pharmaceutical compositions .. The pharmaceutical compositions may contain from 0.1 to 99.9% w/w of invented compound. The carrier must of course be 'acceptable' in the sense of being compatible with the other ingredients of the composition.

The carrier may be a solid or a liquid, and is preferably formulated with an invented compound as a composition in the form of a discrete dosage unit, for example a tablet. Other pharmacologically active substances may also be present in compositions of the present invention. The invented compounds may be incorporated in the compositions either in the form of a base or an acid addition salt thereof, but preferably as the • may be latter, and the compositions^formulated by any of the well-known techniques of pharmacy consisting basically of admixture of components of the composition.

For oral administration, fine powders or granules of the invented compounds may contain diluents and dispersing and surface active agents, and may be presented in a draft, in water or in a syrup; in capsules or cachets in the dry state; in an aqueous or non-aqueous suspension, when a suspending agent may also be included; in tablets, preferably made from granules of the active ingredient with. a diluent, by compression with binders and lubricants; or in a suspension in water or a syrup or an oil or in a water/oil emulsion, when flavouring, preserving, suspending, thickening and emulsifying agents may also be included.

The granules or the tablets may be coated, and the tablets may be scored. The invented compounds may also be administered rectally in the form of a suppository.

For parenteral administration, for example, intramuscular injection, the invented compounds may be presented in unit dose or multi-dose containers in aqueous or non-aqueous injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the compounds isotonic with the blood; or in aqueous or non-aqueous suspensions when suspending agents and thickening agents may also be included; extemporaneous injection solutions and suspensions may be made from sterile powders, granules or tablets which may contain diluents, dispersing and surface active agents, binders and lubricants.

The invented compounds may be administered at a dose rate of from 1 to 30 mg. per kilogram body weight, a suitable dose regimen in man', being from 100 mg. to 2 g. per day, preferably administered in discrete^ dosage - unit form of pharmaceutical compositions; each unit containing conveniently from 10 to 500 mg.

The presen Invention may therefore be summarised as comprising:- (a) The compounds of formula (I) and acid addition salts thereof. (b) The synthesis of the invented compounds by the methods described herein. (c) Pharmaceutical compositions containing an invented compound in association with a carrier therefor; and a method of making such compositions comprising th© admixture of the invented compound with the carrier.

- - The following are examples of this invention, but these are not to be construed as limiting of its scope. All temperatures are in degrees Celsius.

Example 1 A mixture of 1-aminoisoquinoline (2.9 g., 0.02 mole) and methy acrylate (1.8 g. , 0.02 mole) was heated on a steam bath for 1 hour. A homogeneous melt initially formed which crystallised after about 20 minutes. Recrystallisation from ethanol gave pure 3 , 4-dihydro-2-oxo-2H-pyrimido — { 2 , 1-a) isoquinoline, m. p..209-211°.

Example 2 Methyl acrylate (1.8 g. , 0.02 mole) was added to l-amino-3 , 4-dihydroisoquinoline (2.9 g., 0.02 mole). An exothermic reaction occurred and the reaction mixture rapidly crystallised. The solid mass was heated on a steam bath for a further hour to ensure complete reaction.

Recrystallisation from ethanol gave pure 2-οχό-3 , 4 , 6 , 7-tetrahydro-2H-pyrimido{ 2 , 1-a} isoquinoline, m.p. 175-177°.

Example 3 .· · A mixture of 1-aminoisoquinoline (2.9 g., 0.02 mole) and ethyl β-chloroproprionate (2.7 g. , 0.02 mole) was heated on a steam bath for 3 hours. The heterogeneous mixture was dissolved in hot ethanol. On cooling, crystals of crude 3, 4-dihydro-2-oxo-2H-pyrimido{ 2 , 1-a} isoquinoline hydrochloride , m.p. 279-281°, separated.' Recrystallisation from ethanol gave pure 3 , 4-dihydro-2-oxo-2H-pyrimido{ 2 , l-a}isoquinoline hydrochloride, m.p. 292-294°. .

Example 4 3- (1 , 2-Dihydro-l-iminoisoquinol-2-yl ) propionic acid (2.2 g., 0.02 mole) was dissolved in 40 ml. of concentrated hydrochloric acid and heated on a steam bath for 2 hours.

The reaction mixture was evaporated to dryness, leaving the crude hydrochloride salt of the product.

Recrystallisation from aqueous ethanol gave pure 3 , 4-dihydro-2-oxo-2H-pyrimido{ 2 , 1-a} isoquinoline hydrochloride m.p. 293-295°.

Example 5 2-oxo-l , 3 , 4·, 6 , 7~llb~hexahydro-2H-pyrimido-{ 2 , 1-a} — isoquinoline, prepared by the method of Beke and Tflke (Chem. Ber . , 1962, 9J3, 2122-2131), was heated with palladium black for 4 hours at 180°. Fractional crystallisation from methanol gave 3 , 4-dihydro-2-oxo~2H-pyrimido{ 2 , 1-a} isoquinoline m.p. 207-209°.

Example 6 1,3,4,6,7 , llb-Hexahydro-2-oxo-2H-pyrimido{ 2 , 1-a}— isoquinoline (500 mg, 0.0025 mole) was dissolved in chloroform (2 ml.) and a solution of iodine (1 g.) in chloroform (5"0" ΐ.) was added. The brown crystals which separated were removed by filtration and treated with chloroform and 2 sodium hydroxide solution. On evaporation the chloroform extract gave crude 2-oxo-3 , 4 , 6 , 7-tetrahydro-2H-pyrimido{ 2 , 1-a} — isoquinoline, which on recrystallisation from acetone melted at 168-172°. ' / Example 7 ■ •' 3- (1 , 2-Dihydro-l-iminoisoquinol-2-yl) propionic acid was prepared by the following two methods. (a) 1-Aminoisoquinoline (2.9 g., 0.02 mole) and acrylic acid (1.4 g., 0.02 mole) were heated under reflux in water (20 ml.) for 4 hours. Evaporation to dryness under reduced pressure left a thick gum. On treatment with boiling ethanol, the gum dissolved and cream crystals of pure '3- (1 , 2-dihydro-l-iminoisoquinol-2-yl) propionic acid (m.p. 174-175°) separated.

J (b) A solution of propiolactone (0.7 g. , 0.01 mole) in 5 m of acetone was added to a solution of 1-aminoisoquinoline (1.4 0.01 mole) in acetone (10 ml.) at room temperature. After 24 Example 8 A mixture of 1-aminoisoquinoline (1.4 g., 0. 01 mole) and methyl acrylate (1.8 g. , 0.02 mole) was heated on a steam bath for 1 hour. An homogenous melt initially formed from which some crystalline material slowly separated. The reaction mixture was dissolved in boiling ethanol. and crystals of pure 3 , -dihydro-2-oxo 2H-pyrimido{ 2 , 1-a} isoquinoline , m.p. .209-211°, separated on cooling.

Example 9 A solution of 1-aminoisoquinoline (1.4 g. , 0.01 mole) in 20 ml of ethanol and methyl acrylate (0.9 g. , 0.01 mole) was heated under reflux for 2 hours. On cooling, crystals of pure 3 , 4-dihydro,-2-oxo-2H-pyrimido{ 2 ,2-a} isoquinoline , m.p. 210-212°, separated.

Example 10 A solution of 1-aminoisoquinoline (.1.4 g. , 0.01 mole) in 20 ml of toluene and methyl acrylate (0.9 g., 0.01 mole) was heated under reflux for 2 hours. The resulting solution was decanted from a small amount of black gum. On cooling, crystals of crude. 3,4-dihydr 2-oxo-2H-pyrimido{ 2 , 1-a} isoquinoline , m.p. 120-140°, separated. Recrystallisation from ethanol gave pure material, m.p. 209-211°.

Example 11 A mixture of 1-aminoisoquinoline (2.9 g. , 0.02 mole) and n-butyl acrylate (2.6 g., 0.02 mole) was heated on a steam bath for 1 hour. An homogenous melt initially formed which crystallised, after about 20 minutes. Recrystallisation from ethanol gave pure 3 , 4-dihydro-2-oxo-2H-pyrimido{ 2 , 1-a} -isoquinoline , m.p . 209-211° .

. . ■ . Example 12 A mixture of 1-aminoisoquinoline . (1.4 g., 0.01 mole) and ethyl- -bromopropionate (1.8 g., 0.01 mole) was heated on a steam bath for 3 hours. The heterogeneous mixture was dissolved in hot ethanol. On cooling, crystals of crude 3 ,4-dihydro-2-oxo-2H-pyrimido— {2 ,l-a}isoquinoline hydrobromide, m.p. 190-192°. Two further recrystallisations from aqueous ethanol gave pure 3 , 4-dihydro-2-oxo- 2H-pyrimido{ 2 , 1-a} isoquinoline hydrobromide , m.p. 285-290°.

Example 13 3- (1 , 2-Dihydro-l-iminoisoquinol-2-yl) propionic acid (2.2 g., 0.01 mole) was fused on a steam bath with p-toluenesulphonic acid (1.7 g. ,,.0.01 mole) for 2 hours.. The residual gum on recrystallisation from e'thaaol gave pure 3 ,4-dihydro-2-oxo-2H-pyrimido-{2 ,1-a}- isoquinoline p_-toluenesulphonate , m.p. 180-182°.

EXAMPLE 1-4 A tablet formulation for pharmaceutical use was prepared as follows : A mixture of 3 , 4-dihydro-2-oxo-2H-pyrimido {2,1-a)— isoquinoline hydrochloride (lO mg of the base) , Starch, .P. (25mg) and Lactose, B.P. (200mg) , was granulated with a 1G solution of hydrolysed starch ClOmg starch in all) in purified water B.P. Af er drying the granules at 50°C, Starch B.P. (25ng) and Magnesium Stearate, B.P. (5mg) we::e added. The final mixture was compressed into tablets.

" EXAMPLE Γ5 A tablet formulation- for pharmaceutical use vms prepared as follows : .. A mixture of 2-oxo-3 , 4 , 6 , 7~tetrahydro-2H~pyrimido— {2Tl-a) isoquinoline hydrochloride (lOOmg of the • base) , Starch, B.P. (25mg) and Lactose, B.P. (200mg). .: was granulated with a 10% solution of hydrolysed .' starch (lOmg starch in all) in purified water B.P.

After drying the granules at 50°C , Starch B.P. : ■■· (25mg) and Magnesium Stearate, B.P. (5 mg) were • added. The final mixture was compressed into tablets . t!. P. JACKSON

Claims

A 357A - 14 - What we claim is :

1. A process for the preparation . of a compound of formula wherein X rogen atom or together they form an additional bond, or an acid addition salt thereof, in which proces one k) reacts a compound of the formula as before, with an alkyl acrylate ester of formula CH2=CH — COOR wherein R is an alkyl group having 1 to 6 carbon atoms; (b) reacts a compound of the formula wherein X and X have the same meaning as before with a β-substituted propionate ester of formula Z A 357A - 15 - wherein R is an alkyl group having 1 to 6 carbon atoms' and Z a nucleophilx'c atom or group; (c) cyclises a compound of formula (d) oxidises a compound of formula A 357A - 16 -

2. A process as claimed in claim 1 (a) in which the reaction is carried out in the presence of a solvent.

3. A .process as claimed in claim 2 in which the solvent is a polar solvent/

4. A process as claimed in claim 1(a) in which the alkyl group a primary alkyl group.

5. A process as claimed in any of claims 1(a) and 2 to 4 in which the alkyl acrylate ester is present in excess of the molar ratio.

6. A process as claimed in claim 1(b) in which the nucleophilic atom is selected from the class consisting of bromine, chlorine * and iodine. . . .

7. A process as claimed in claim 1(b) in which the nucleophilic group is the p_-toluenesulphonyl group. . ■

8. A process as claimed in any of claims 1(b) , 6 and 7 in which the alkyl group is a primary alkyl group.

9. A process as claimed in any of claims 1(b) and 6 and Q-in which the β-substituted propionate ester is ι present in excess of A 357A - 17 -

10. A process as claimed in claim 1(c) in which the cyclisation is effected by heating of the compound to a temperature above its melting point.

11. A process as claimed in claim 1(c) in which the cyclisation is effected by use of an acid, optionally with heating of the reage

12. A process as claimed in claim 1(c) in which the acid is a concentrated mineral acid or a strong organic acid.

13. A process as claimed in any of claims 1(c) and 10 to 12' in which an intermediate compound of formula in which X before, is prepared by the reaction of a compound of formula wherein Χ and ^ have the same meaning as before, with α,β-unsaturated- ■· or 8-hydroxy- propionic acid, or β-propiolactorie .

14. A process as claimed in claim 13 in which the intermediate compound is prepared in situ.

15. A process as claimed in either of claims 13 and 14 in which the reaction is carried out in the presence of a solvent.

16. A process as claimed in claim 15 in which the solvent is a polar solvent. . ' '. ' ■ ..

17. A process as claimed in claim 16 in which the polar solvent is water. A 357¾ - 18 -

18. A process as claimed in claim 16 in which the polar solvent an aliphatic ketone.

19. A process as claimed in claim 1(d) in which one oxidises a compound of formul by heating at an elevated temperature with a palladium catalyst as to yield 3 , 2 , 1-a} isoquinoline .

20. A process as claimed in claim 1(d) in which one oxidises a compound of by reaction with iodine at room temperature soras to yield 3,4,6 Tetrahydro-2-oxo-2H-pyrimido{ 2 , 1-a} isoquinoline . A357 A - 19 - 21. A process as claimed in any of claims 1 to 20 in which one converts a cormoound of formula wherein X and X have the same meaning as before, to an acid addition salt thereof.

22. A process as claimed in any' of claims 1 to 20 in which one converts an acid addition salt of a compound of formula wherein X and X .have the same meaning as before, to another acid addition salt', by double decomposition.

23. A process as claimed in claim 22 in which double decomposition is effected in an ion exchange column.

24. A process as claimed in claim 22 in which double decomposition is effected in solution. , '

25. A process as claimed in any of claims 1 to 20 in which one converts an acid addition salt of a compound of formula wherein X and X have the same meaning as before, into the free base. A 357 Al - 20 - ^

26. A process for the preparation of a pharmaceutical composition comprising admixture of a compound of formula wherein X and X are each a hydrogen atom or together form an additional bond or a pharmaceutically acceptable acid, addition salt, with a pharmaceutically acceptable carrier therefor.

27. A process for the preparation of a pharmaceutical composition as claimed in claim 26 comprising admixture of 3 , 4-Dlhydro-2-oxo-2H-pyrimido^{2 , l-a}isoquinoline or a pharmaceutically acceptable acid addition. salt thereof, with a pharmaceutically acceptable carrier therefor .

28. A process for the preparation of a pharmaceutical composition as claimed in claim 26 comprising admixture of 3 , 4 , 6 , 7-Tetrahydro-2-oxo-2H-pyrimido{ 2 , 1-a} isoquinoline or a- harmaceutically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier therefor. . - 29."' A process as claimed in any of claims 26 to 28 wherein the acid addition salt is a hydrogen halide salt. A 357B wherein X and X are each a hydrogen atom or together form an addition bond, or an acid addition salt thereof.

31. An isoquinoline as claimed in claim 30 in the form of a pharmaceutically acceptable acid addition salt thereof.

32. 3 , 4-Dihydro-2-oxo-2H-pyrimido{ 2 , 1-a} isoquinoline or an acid addition salt thereof.

33. 3,4,6 , 7-Tetrahydro-2-oxo-2H-pyrimido{ 2 , 1-a} isoquinoline or an acid addition salt thereof.

34. An isoquinoline as claimed in claim 32 or 33 in the form of a hydrogen halide acid addition salt thereof. A 357 Bl . - 22 -·■ · . .' ^

35. A pharmaceutical composition comprising an isoquinoline and or a pharmaceutically acceptable acid addition salt thereof, as . an claimed in claim 1, in admixture with^ acceptable carrier therefor.

36. A pharmaceutical composition as claimed in claim 35 suitable for oral or rectal administration and in the form of a discrete dosage unit containing from 10 mg to 500 mg of the isoquinoline compound or acid addition salt thereof.

37. A pharmaceutical composition as claimed in claim 35 suitable for parenteral administration and in the form of an injection solution or suspension. A 357 B2 - 23 -

38. Am isoquinoline or an acid addition salt thereof as claimed in any of claims 30 to 34 when prepared by . a process as claimed in any of claims 1 to 25. 39 '., A pharmaceutical composition as claimed in "any of claims 35 to 37 when prepared by a process as claimed in any of claims 26 to 29.. A 357 B3 - 24 -

40. A method of pre noline of formula wherein X and X are each a hydrogen atom or together form an additional bond, or an acid addition salt thereof, substantially as described hereinbefore with particular reference to Examples 1 to 13. 41. A pharmaceutical composition of an isoquinoline of formula wherein X" and X" are each a hydrogen atom or together form an additional bond, or a pharmaceutically acceptable acid addition salt thereof, substantially as described hereinbefore with particular reference to Examples 14 and 15.

42. A method of preparing a pharmaceutical composition of an isoquinoline of 1 wherein X and atom or together form an additional bond, or a pharmaceutically acceptable acid addition salt thereof . substantially as described hereinbefore with particular reference to examples 14 and 15. For the Applicants DR. mufyifcpm By: (;